title: Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide.
abstract: Artemis deficiency is known to result in classical T-B- severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T-B- SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5' splice-site or an intronic point mutation creating a novel 3' splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3' splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Ijspeert
authors.forename: A C
authors.initials: AC
authors.lastname: Lankester
authors.forename: J M
authors.initials: JM
authors.lastname: van den Berg
authors.forename: W
authors.initials: W
authors.lastname: Wiegant
authors.forename: M C
authors.initials: MC
authors.lastname: van Zelm
authors.forename: C M R
authors.initials: CM
authors.lastname: Weemaes
authors.forename: A
authors.initials: A
authors.lastname: Warris
authors.forename: Q
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.forename: A
authors.initials: A
authors.lastname: Pastink
authors.forename: M J D
authors.initials: MJ
authors.lastname: van Tol
authors.forename: J J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: D C
authors.initials: DC
authors.lastname: van Gent
authors.forename: M
authors.initials: M
authors.lastname: van der Burg
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D020320:Oligoribonucleotides, Antisense / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D017422:Sequence Analysis, DNA; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020320:Oligoribonucleotides, Antisense; D022821:RNA Splice Sites; C426344:DCLRE1C protein, human; D004720:Endonucleases